The muskie, unlike the northern pike, has six to nine pores (usually seven) on each side of the underside of the lower jaw. The lower half of the muskie's cheek is not scaled. The lobes of the muskie's tail are more pointed than those of the northern pike.

The muskie's coloration, too, is distinct from a northern pike's and takes three common forms that depend somewhat on the muskie's place of origin, but all have a light background.

Most muskie from the upper Mississippi watershed have dark spots on a light background. Muskie from the Park Rapids area and ShoepackLake in VoyageursNational Park (as well as many Wisconsin waters) usually have dark bars on a light background. The Shoepack strain was widely stocked until it was discovered to be a rather small fish, even when raised in waters suited for rapid growth.

The third pattern, which is occasionally seen throughout Minnesota and Wisconsin, is the "clear" pattern of light sides with no marks or very faint marks on the rear third of the fish.

The muskie spawns when the water temperature is 48 to 59 degrees, about two weeks later than the northern pike. A 40-pound female can produce more than 200,000 eggs. They generally spawn twice, the second time about 14 days after the first time. Unlike the northern pike's adhesive eggs, which cling to vegetation, the muskie's eggs settle to the bottom, rather than the weedy in-shore areas northern pike use. This separation of spawning areas apparently prevents northern pike fingerlings from preying on newly hatched muskie fry. In other circumstances, however, late-spawning northern pike have been observed actively spawning with muskie; the hybrid offspring is called a "tiger muskie."

The muskie's diet is similar to the northern pike's. Fry eat plankton and then invertebrates but soon eat primarily fish. Muskie feeding peaks at water temperatures in the mid-60s and drops off as temperatures reach the mid-80s.

Muskie are smaller than northern pike during their first couple years but later grow longer and heavier than their relatives, occasionally surpassing 30 pounds. The average angler-caught muskie is much larger than the average northern pike. Genetics plays a role in this size difference. So do fishing regulations that protect muskie with a minimum-size limit but allow a liberal harvest of small to medium-size limit but allow a liberal harvest of small to medium-sized northern pike.